Neurosurgery and Neuroscience

Oscillations of cytosolic Ca2+ are necessary for cellular signaling and propagation of Ca2+ signal is an absolute requirement for the functioning of neuronal cells. Ca2+ appears to be a universal and ubiquitous signaling molecule, thereby in resting neuronal cells its concentration is kept at ~100 nM against 1-2 mM outside the cell. Inability to maintain calcium homeostasis in neurons underlies many neuropathologies. Ca2+ may elicit a variety of diff erent responses based on the type of targeted neurotransmission pathways, and it regulates synaptic plasticity, controls neuronal growth and neuronal survival. The plasma membrane contains a high affinity Ca2+-ATPase (PMCA) that translocates Ca2+ from the cytosol to the extracellular environment. The enzyme is coded by four separate genes (PMCA1-4), among which PMCA2 and PMCA3 are considered as neuron-specific forms. In the brain, PMCA function declines progressively during aging, thus impaired calcium homeostasis may contribute to neurodegeneration. We have developed the stable transfected differentiated PC12 cells with reduced level of PMCA2 or PMCA3, and the most critical finding was permanently increased resting Ca2+ concentration. Altered PMCA composition affected the expression level of several Ca2+-associated proteins (SERCA, calmodulin, calcineurin, neuromodulin) and certain types of voltage-gated calcium channels. We have also evidenced a novel PMCA role in regulation of bioenergetic pathways and mitochondrial activity. Interestingly, some changes could occur as adaptive processes protecting cells against calcium overload. Since age-related PMCA decrease has been documented, our modified PC12 cells may be a useful model to clarify the biological changes in neurons as well as to study the vulnerability of cells to neurodegenerative insults.